An estimated 25 million Americans have osteoporosis. Senile osteoporosis is caused by inadequate bone formation relative to resorption, a deficit attributed to an age-related reduction in the number of bone forming cells (osteoblasts). This in turn may be related to an age-related decline in the number of osteoprogenitor cells in the bone marrow. A related problem is the age-related reduction in the ability of the skeleton to respond to mechanical stimuli (i.e., mechanoresponsiveness), which may be part cause and part effect of the osteoblast deficit. While mechanical loading of the skeleton can be a powerful stimulus to form new bone, our understanding of the cellular mechanisms by which loading stimulates bone formation are incomplete and the role, if any, of the marrow progenitors cells is not known . Our overall goal is to assess the responsiveness of the aged/osteoporotic skeleton to increased mechanical loading, with a focus on the role of bone marrow osteoprogenitors. Specifically, in Aim 1 we will use two models of senile osteoporosis, aged BALB/c wildtype mice and stem cell antigen-1 (Sca-1) null mice, both of which have reduced marrow osteoprogenitors and osteoporotic bones. We will subject these mice to two types of loading (tibial bending and low-amplitude, high-frequency whole-body vibration [WBV]) and determine if they have impaired response to loading compared to control animals. In Aim 2, we will make use of whole-body irradiation to directly attenuate marrow osteoprogenitors in wildtype mice, followed by loading. In Aim 3, we will examine the potential of intermittent treatment with parathyroid hormone (PTH) to enhance loading responses in aged BALB/c wildtype and Sca-1 null mice. PTH has actions on marrow osteoprogenitors, is a key regulator of the marrow stem cell niche, and has been shown to act synergistically with mechanical loading. We will pair PTH with low-amplitude WBV to determine if combining these two clinically relevant treatments will lower the therapeutic dose of PTH or enhance the heretofore modest effects of WBV. These studies will clarify the role the marrow plays in supporting loading-induced bone formation and will determine whether or not age-related deficits in osteoprogenitors in the marrow contribute to reduced mechanoresponsiveness in the osteoporotic skeleton. [unreadable] [unreadable] [unreadable]